The overall aim of this research is to define and characterize factors regulating granulocyte production and maturation in humans and to determine whether alterations in regulatory systems can be defined in human hematopoietic disorders. Using the method of bone marrow culture in agar-gel in which single cells can be stimulated to divide and form colonies of maturing granulocytic and monocytic cells, factors affecting granulocyte and monocyte production will be studied. The specific aims are to determine the major cellular source of granulopoietic factors in normal humans. Initial work indicates that this property resides in the monocyte-macrophage system. The study will be aimed at determining the mechanisms and stimuli for production of granulopoietic factors by these cells. Further studies are aimed at determining the biochemical nature of granulopoietic substances previously described and their mechanism of action. Human leukemias are under intense study to determine whether alterations in granulocyte regulating factors exist in these disorders which can be exploited therapeutically. Human aplastic anemia and granulocytopenic states are being studied for alterations in granulopoietic regulation including levels of granulopoietic factors in serum and urine and responsiveness of bone marrow cells from these patients to previously described granulocyte stimulators. Animal modelsof aplastic anemia and granulocytopenia are also under study with the same aims in mind. Levels of granulopoietic factors following chemotherapy are being studied in patients with lymphomas without bone marrow involvement. Inhibitor of previously described granulopoietic factors and determination of their specificity and method of action are also under investigation. Lithium carbonate, a drug known to induce granulocytosis in hematologic normal humans, is being studied for its effect on granulocyte production in vitro in an attempt to determine its method of action and possible therapeutic usefulness in granulocyte disorders. The relationship between granulopoietic factors and B12 binding proteins in serum, urine, and tissues is under investigation.